This KO2 application seeks support that is essential for Dr. Sanacora's continued career development as a newly-independent clinical researcher. Funded by a NIMH K08 mentored career award (K08-MH-01715) Dr. Sanacora has attained considerable expertise in the use of magnetic resonance spectroscopy as a tool to investigate the role of amino acid neurotransmitter systems in the pathophysiology and treatment of mood disorders over the past 5 years. Thanks to the mentorship Dr. Sanacora received and the excellent environment provided to him through the Magnetic Resonance Center and the Department of Psychiatry at Yale he demonstrated considerable research productivity during this time as evidenced by his peer-reviewed publications and a recently-awarded RO1 (MH071676-01, G. Sanacora, P.I.). However, this K08 expired 6/31/04. This KO2 award is vital for sustaining Dr. Sanacora's current full-time research focus and for assuring his successful matriculation into a fully independent investigator. Justification for the award is provided by a comprehensive 5-year Career Development Plan that builds on his current expertise in the study of amino acid neurotransmitter contributions to mood disorders and the MRS methodologies used to investigate this area. Specifically, his goals are to acquire specialized skills in several additional areas that will make it possible for him to extend this work into areas of more direct scientific and clinical significance: 1) 13C-glucose MRS methods to measure rates of synthesis and cycling, 2) 13C-acetate studies to probe glial cell involvement in mood disorder pathology, 3) clinical trial experience to allow him to address the potential clinical usefulness of drugs targeting the amino acid neurotransmitter systems, and 4) basic molecular neurobiology related to amino acid neurotransmission that will enable him to continue to conduct relevant translational research in mood disorders. Intensive training is provided by an integrated curriculum of intramural coursework, extramural didactics, individualized preceptorships, interactive symposia, and research-related organizational meetings. Three representative studies are included to illustrate how the development of these skills will be used to advance the line of research that was initiated in his previous K08 award into the realms of pathophysiology and clinical practice. Thus, receiving this award would allow him the opportunity to improve the basic understanding of how the amino acid neurotransmitter systems and glial cell pathology contribute to the neurobiology of mood disorders. This work has direct clinical relevance since it is likely to lead to the development of novel diagnostic methods and treatment modalities for these disorders. [unreadable] [unreadable] [unreadable]